Loss of memory and cognitive functions are often associated with aging. This is the result of neurodegeneration. However, in some cases, this process of neurodegeneration becomes accelerated due to premature cell death in the brain, leading to a variety of cognitive impairments or dementia. Among these neurodegenerative disorders, Alzheimer's disease (AD) is most prevalent in recent years. It has also attracted considerable attention locally because Prof. Charles K. Kao, former president of the Chinese University of Hong Kong and Nobel Laureate in Physics, 2009, was stricken with this devastating disease.
More than 36 million people worldwide were estimated to suffer from Alzheimer's disease (AD) in 2009 and the patient number was expected to increase to 115 million in 2050. The incidence rate of AD is known to increase with age. At age over 65, the incidence rate is about 5% in the general population. At age over 80, the incidence rate increases to about 20%, i.e., one in five. Current drug treatments can only improve symptoms and produce no profound cure. In recent years, several approaches aimed at inhibiting disease progression have advanced to clinical trials. Among them, strategies targeting the production and clearance of the Aβ peptide, which is thought to be a critical protein involved in the pathogenesis of the disease, are the most advanced.
Aβ peptide is the principal protein component of the Aβ plaques, which are found in the brains of AD patients during autopsy. The occurrence of the Aβ plaques, considered a cardinal feature of AD, provides the only confirmed diagnosis of the disease. Extensive researches in past decades have indicated a central role for the Aβ peptide in the disease process where the Aβ peptides assemble (aggregate) into Aβ fibrils which exert a cytotoxic effect towards the neurons and initiate the pathogenic cascade. Recent studies showed that oligomeric, prefibrillar and diffusible assemblies of Aβ peptides are also deleterious. The ability of this peptide to form Aβ fibrils seems to be largely sequence-independent, and many proteins can form structures with the characteristic cross-β stacking perpendicular to the long axis of the fiber. Although a consensus mechanism for the pathogenic oligomeric assembly has yet to emerge, the idea of finding some brain-penetrating small molecules that can interfere with the interactions among the Aβ peptide monomers and thus inhibit the formation of the neurotoxic oligomers and the resulting Aβ plaques is an attractive approach to treating/preventing the disease. The use of agents that stabilize the monomer, interfere with the aggregation process (amyloidogenesis) and allow for the isolation of the intermediate species will help to elucidate the molecular mechanism of Aβ fibril formation. In addition, imaging agents that can specifically bind Aβ fibrils and plaques in vitro and in vivo are of paramount importance for studying the pathological events of the disease, disease diagnosis and monitoring of therapeutic treatment.
We have previously shown that carbazole-based fluorophores are highly sensitive fluorescent light-up probe for double strand DNA and strongly active two-photon absorption dyes for two-photon excited bioimaging, the disclosure of which is incorporated by reference herein. Recently, the mono-cyanine fluorophore has also been found to exhibit binding affinity towards beta amyloid (Aβ) peptide concomitant with strong fluorescent enhancement. These findings provide us the lead molecular structure to design and synthesize novel functional carbazole-based fluorophores for imaging and inhibition the aggregation of Aβ peptides.
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